In mammals, odorants are detected by olfactory sensory neurons (OSNs) that line the olfactory epithelium (OE) of the nose. OSNs express olfactory receptors, which are G protein-coupled receptors specialized in detecting odors. There are ~1000 OR genes in mice, and ~350 in humans. The large numbers of ORs and the combinatorial activation of those ORs by odorants allow for discrimination of myriad odorants. Recently, however, our lab has found a second family of fourteen chemosensory receptors in the mouse OE. Genes encoding these receptors, called trace amine-associated receptors (TAARs) are present in mouse, human, and fish, and are found in both the fish and mouse OE. Like ORs, individual mouse TAARs is expressed in unique subsets of OSNs that express only that receptor. Screening of TAARs with diverse odorants revealed ligands for several TAARs, all of which are small volatile amines. Interestingly, at least three mouse TAARs recognize amines found in urine. One detects a compound linked to stress while the other two detect compounds enriched in male versus female urine. The evolutionary conservation of the TAAR family suggests that this family may have a chemosensory function distinct from ORs. Ligands identified for TAARs thus far hint at a function associated with the detection of social cues. In the proposed studies, we will further investigate the roles played by TAARs in the mouse. First, we will use calcium imaging to test individual TAARs expressed in tissue culture cells for responses to mouse secretions obtained from mice of different sex, age, reproductive status, stress levels, and genetic background. Next, we will examine how TAAR signals are organized in the olfactory bulb using radioactive TAAR probes to label mRNAs in OSN axons. Finally, we will test whether TAAR ligands we have identified can stimulate physiological effects in mice. PUBLIC HEALTH RELEVANCE: TAARs are a newly found family of receptors conserved from fish to humans that may detect social cues. Hence, this work in mice will ascertain whether certain odor cues recognized by TAARs can cause innate responses in emotion and physiology, implicating a novel ability to sense odor cues in human social contexts.